The global syndemic interaction between the acquired immunodeficiency syndrome (AIDS) and tuberculosis (TB) epidemics has deadly consequences. One third of the 38.6 million people infected with HIV are co-infected with Mycobacterium tuberculosis (Mtb), resulting in TB being the largest single cause of death in AIDS patients. However, the mechanism(s) that mediates loss of Mtb control in TB/HIV co- infected hosts are not known. HIV-induced decline in CD4+ T cells correlates with increased susceptibility to TB. In addition, HIV-induced CD4+ T cell depletion may also occur within the lung granuloma, impairing Mtb control, and facilitating progression from latent TB (LTBI) to Pulmonary TB (PTB). Thus, although the granuloma is considered important for Mtb control, the immunological differences between a protective granuloma seen during LTBI, and a non-protective granuloma seen during PTB have not been described until recently. Our recent work in human, Nonhuman primate (NHP) and mouse models of TB, has demonstrated a role for inducible Bronchus Associated Lymphoid tissue (iBALT) in TB. iBALT contains spatially organized T cells, B cells and macrophages and its presence is associated with better protective outcomes during TB. In addition, our new published data show that in PTB, a dominant feature of the granulomatous inflammation is the accumulation of neutrophils that produce inflammatory molecules such as S100A8/A9 proteins. Incidentally, increased neutrophil accumulation has also been recently associated with increased Mtb and viral burden in TB/HIV co-infected patients. Based on these new data, we propose the paradigm-shifting hypothesis that a protective TB granuloma is one that contains iBALT and contributes to Mtb containment during LTBI. In contrast, progression to a more neutrophilic, inflammatory granuloma causes TB reactivation, loss of Mtb control and progression to PTB. In this proposal, we will test this overall hypothesis through three specific Aims. In Aim 1, using mouse and NHP models of TB, we will mechanistically identify Mtb genes and pathways that modulate iBALT formation, providing crucial new information about the mechanism(s) employed by Mtb in interfering with the formation of protective iBALTs. In Aim 2, we will address the functional role of persistent iBALT in limiting reactivation and dissemination in latently infected mice. In addition, we will also address the relevance of CD4+ T cells in iBALT function using the NHP model of TB/SIV co-infection. In Aim 3, we will determine whether iBALT structures can be enhanced, or neutrophilic granulomas reversed, to decrease TB reactivation and disease severity during latency and SIV co-infection. Together, these aims will provide new information on the clinical relevance of iBALT in latency, reactivation of TB, and identify novel HDTs to decrease TB reactivation rates, particularly in a setting of HIV co-infection. Without doubt, any decrease in global TB burdens will also significantly decrease the deadly consequences of the HIV-TB syndemic.